Heritability for stroke: Essential for taking family history

Background: There are many well-established factors that influence the risk of stroke including blood pressure, diabetes, low socioeconomic status and smoking, however, the shared genetic resource in members of a family effect on stroke predisposition. Genome-wide association studies (GWAS) have demonstrated evidence of a shared genetic source in stroke risk. This review considered the influence of family history as one of the main risk factors in stroke according to the literature. Methods: Literature review was obtained by searching for the key words "stroke", "family history" and "stroke gene" in PubMed. An overview has been made on the topics: relevance of stroke family history, family history assessment tools and specific candidate genes for stroke. Results: Family history of stroke is an important risk factor for the development of cerebrovascular diseases in addition to stroke subtypes in relatives who have reached the questionnaire and pedigree. While variation in a small number of loci showed Mendelian inheritance of stroke phenotypes, the genetic variations in several stroke risk loci are shared with multiple related vascular traits. Conclusion: This study highlighted the importance of family history in stroke phenotypes and current related genetics information. Increasing awareness of the importance of family history in stroke has the advantage of preventing exposure to stroke with health care.

S troke is an acute neurological event that has been characterized by loss of motor, sensory and cognitive function (1,2). Strokes occur when blood flow to the brain breaks down. There are three main types of stroke including ischemic, hemorrhagic and transient ischemic attack. Nearly 20% of strokes are hemorrhagic, causing bleeding in the brain (3). Some of the major treatable risk factors for stroke are: hypertension, cigarette smoking, signs of heart disease or history of stroke, diabetes, imbalance of cholesterol, physical inactivity and obesity (4). A risk factor is a situation or behavior that usually occurs in those who develop a higher risk of having a disease than those who do not (5). By increasing the number of risk factors, the risk of stroke increases. Therefore, it is essential to develop well-organized methods to prevent or reduce the occurrence of stroke (6). Recent progress in the treatment of stroke, in addition to the control of certain risk factors such as blood pressure, salt intake, weight and smoking can reduce the tendency of mortality (7). However, some factors for stroke cannot be changed by medical treatment or lifestyle changes. Although the greatest attention has been focused on environmental effects and lifestyle, since they can be adapted and controlled, it has been documented that the stroke also has a hereditary base that can interact with environmental factors (8). The family history of a premature stroke is an independent risk factor for stroke inheritance and with greater force in subjects between 25 and 49 years (9, 10).

Pourasgari M, et al.
Inheritance is an estimated measure of the genetic contribution to the total phenotypic trait (11,12). Therefore it has been shown that a positive family history of stroke may be a signal for the onset of stroke at a younger age; however, large variations in age at onset indicate that environmental elements are also important in determining whether a person can progress with stroke (1,(13)(14)(15). To advance our understanding of the effects of genetics and the aggregation of family history as a risk factor in stroke, we have summarized the recent findings in these characters. Acquisition of evidence: The Medline literature was searched by the key words "stroke", "family history", "pedigree" and "stroke gene" until August 2018 to study the genetic risk factors for stroke. A narrative overview was performed on the relevance of family history in stroke and family history assessment tool. Further revisions have been recognized by examining the appropriate bibliography to which reference is made in the original documents. Family history report to caress: Several prospective cohort and case-control studies have examined the coherent relationship in the family history of stroke (9,10,13,14). The results of these studies are sometimes inconclusive and may be the consequence of alterations in the design of the study, approaches to the recognition of stroke in family members, insignificant sample size or selection of the study population (14,16). Population-based prospective cohort studies have shown a positive family history as a risk factor for stroke development. Family history was more strongly associated with young age in both hemorrhagic and ischemic stroke. However, as people grow older, there are fewer effects of a family history and genetic factors at the stroke risk (14,17,18). Nonetheless, an increased risk of stroke has been reported in those children who have a family history of stroke before age 65 (9). It has been shown that the presence of a family history of stroke in at least one parent doubled the risk of stroke among men and increased the risk among women (18)(19)(20). In this way, a stroke history in a sibling is also an increased risk of stroke in a proband (17). Female patients are more expected to have a stroke of first degree in particular with maternal history than in male patients (20). However, there is no variation of the paternal with the maternal history of stroke in male probands (20). Genetic factors, related to age under environmental impacts, explain sex differences due to the risk of stroke. An increasing risk of stroke is also observed in monozygotic twins compared to dizygotic twins or siblings (13). However, rare models of Mendelian stroke are also reported in monogenic disorders of sickle cell anemia and Fabry's disease (5,21). Tools for collecting the family history: Clinical disorders in adults indicating family inheritance may progress or delay the onset of the disease in adjustments to environmental factors (22,23). Genetic variants allow the accumulation of phenotypes of familial diseases in individuals of a given population. The achievement of family history is a record of information on the health of the person participating as the main point of a family (proband) and its close relatives for genetic study and the cause of death in three generations (24). Family history analysis provides risk assessment in primary care practices and helps screening, diagnosis and early therapy, which can prevent or improve disease outcomes in individuals and their close relatives and suggests an opportunity for promotion of health (23,24). Several methods have been recognized for obtaining family clinical histories, each with its specific advantages and disadvantages (25). The family history questionnaire that provides more accurate information is the usual approach in general practice. The appropriate response on the questionnaire is verified by the health care provider for further information including the relationship of the family members with the patient, the accurate identification, age of onset and severity of the disease. Another tool for evaluating the family history used by the genetic counselor is the pedigree. A family tree preferably shows at least three generations with the use of standardized symbols. This tree obviously identifies affected individuals with a specific diagnosis. A family tree indicated the age of the individuals, the age and causes of death in the deceased and any appropriate clinical history or illness (23). The results of any genetic testing of family members, if it has been achieved, should be indicated on the pedigree. The pedigree analysis of populations of unselected patients regularly reveals numerous genetic risk factors that were not previously recognized (21,26,27). The presence of a younger firstdegree relative affected by family history could increase the risk of illness two to five times in the general population, however, a strong family history of a dominant trait may bring the risk of a disease to 50% or others (28).

Genetic variations that influence stroke heritability:
Stroke is a polygenic disease that is influenced by multiform mechanisms of the interaction of genetic and non-genetic factors (29). Genome-wide research has exposed strokerelated genes, with the function of development and regeneration of the peripheral nervous system, in the inheritance of intracerebral hemorrhage and ischemic stroke (30). However, due to the complexity of gene-gene and gene-environment interactions, they are not applied in clinical practice. Most of the family genetic studies have been conducted in European descendants, so the distribution and heritability of stroke may be different among the ethnic groups (31). A meta-analysis of multi-ancestry genome-wide association on approximately 8 million single nucleotide polymorphisms (SNPs), revealed SNPs with a minor allele frequency (MAF) ranged from 0.6% to 1.8% involved in stroke, although some showed a specific association for the particular population (32). The majority of stroke loci recognized in this meta-analysis showed a common genetic association with other vascular traits. These loci have potent association with cardiac mechanisms further than those of cardioembolism that is not previously implicated in stroke pathophysiology (32).
Mutations in three loci of HTRA1, COL4A1 and COL4A2 genes influence Mendelian inheritance for stroke phenotypes (33)(34)(35). However, common variants such as the A222V polymorphisms in Methylenetetrahydrofolate reductase, E298D of nitric oxide synthase (NOS3), R506Q mutation of the factor V Leiden and G20210A nucleotide substitution of prothrombin contribute to the risk of stroke. The polymorphism in the intron 16 of the angiotensinconverting enzyme (ACE) gene is an independent risk factor for spontaneous intracerebral hemorrhagic stroke (36). The genetic markers rs11833579 and rs12425791 on the 12p13 chromosome near or inside the NINJ2 gene are hereditary causes of family aggregation of stroke in the linkage analysis (37). Furthermore, the polymorphisms and haplotypes of TGF-β1 are significantly associated with the risk of ischemic stroke in the population of northern India (38). The loci rs2280887 and rs4376531 belonging to the ARHGEF10 protein coding gene are associated to atherothrombosis and ischemic stroke (39). The 3 prime UTR variant rs2507800 of ANGPT1 gene is involved in the stroke by interfering to the binding to miR211 (40).
As a result, the risk of stroke within these loci estimates the hereditary risk and the potential of stroke genetics for the discovery of new drugs. Significant locations in the candidate genes for stroke risk that are mostly reported in the previous study (32)(33)(34)(35)(36)(37) are listed in table 1, which shows the heritability of genetic variation as a risk factor for stroke syndrome.
In conclusion positive family history is the main risk factor for stroke at a young age. There are some conventional methods that deal with family medical histories, including the questionnaire and pedigree, which must be customized to prevent or reduce the risk of hereditary stroke. Although the hereditary medical condition is typically caused by monogenic disorders, genome studies in a series of prospective cohort and case-control studies have identified several genetic loci involved in stroke that make the role of family history questionable. Stroke risk loci shared genetic variations with multiple vascular diseases that significantly deepened in pharmacological targets for antithrombotic therapy. Despite numerous studies, investigations on inheritance of stroke require more genetic research to support the suggested role of the genetic component in stroke etiology in individuals with a positive family history.